Cell manipulation method based on thin film resonator and microchip

Abstract

The invention provides a cell manipulation method based on a thin film resonator and a microchip, and the cell manipulation method comprises the steps: arranging a liquid containing cells on a thin film of the thin film resonator, and driving the thin film to vibrate according to a preset resonance mode; and a vortex field is formed in the liquid through film resonance, and the cells are dragged to move towards a stress balance point of the vortex field above an antinode, so that the patterning control of the cells is realized. According to the invention, the resonance mode of the thin film resonator is controlled through the driving frequency of the electric signal to manipulate cells, so that the cell manipulation speed and the cell manipulation precision are improved; meanwhile, an eddy current field is generated through resonance to realize cell manipulation, direct contact with cells is avoided, the original state of the cells can be kept, and unnecessary cell stimulation and damage are avoided; and finally, array manufacturing of the microchip is realized by adopting a micromachining process, parallel manipulation of a large number of cells can be realized, and the cell patterning complexity and manipulation efficiency are improved.

Description

Technical Field

[0001] The invention belongs to the biological field and the microchip field, and in particular relates to a cell manipulation method and a microchip based on a thin film resonator. Background Art

[0002] Cell micromanipulation technology allows precise manipulation of cells at the micrometer or even nanometer scale, and can study the behavior, function, and interaction of cells under specific conditions, which helps to understand the role of cells in tissue formation, development, and disease processes. In terms of biosensors, cell patterning technology can precisely position cells on the sensor surface, thereby improving the sensitivity and specificity of the sensor, and can be used in environmental monitoring, food safety, and medical diagnosis. In terms of drug screening and toxicity testing, cell patterning technology can be used to evaluate the effects of drugs on cells, more effectively screen out drugs with therapeutic potential, and reduce costs in the drug development process. Therefore, cell micromanipulation and patterning play an important role in many fields such as cell biology, drug screening, and biosensors.

[0003] Although a variety of cell micromanipulation and patterning technologies have been developed, most methods require direct contact with cells or introduce unnecessary stimulation, which affects the physiological state of the cells themselves and even causes damage and destruction to the cells; or can only manipulate individual cells one by one, and the manipulation efficiency of a large number of cells is low; or the manipulation speed is slow and the manipulation accuracy is poor, resulting in the existing cell manipulation and patterning technologies still unable to meet current needs. Therefore, there is an urgent need for a structure or method that can quickly, parallelly, and non-destructively manipulate and pattern a large number of cells.

[0004] It should be noted that the above introduction to the technical background is only for the convenience of providing a clear and complete description of the technical solutions of the present application and for the convenience of understanding by those skilled in the art. It cannot be considered that the above technical solutions are well known to those skilled in the art simply because these solutions are described in the background technology part of the present application. Summary of the invention

[0005] In view of the above shortcomings of the prior art, an object of the present invention is to provide a cell manipulation method and microchip based on a thin film resonator, so as to solve the problems of large impact on cells and low patterning efficiency in the existing cell manipulation technology.

[0006] To achieve the above object, the present invention provides a cell manipulation method based on a thin film resonator, the cell manipulation method comprising:

[0007] Placing a liquid containing cells to be patterned on a thin film of a thin film resonator so that the thin film is located in the liquid;

[0008] A preset excitation signal is applied to the thin film resonator to drive the thin film resonator to vibrate in a preset resonant mode; the resonance of the thin film forms an eddy field in the liquid, and the preset resonant mode of the thin film includes two or more antinodes arranged in a preset pattern, and the antinode is the point where the amplitude of the thin film in the preset resonant mode is the largest; the eddy field formed in the liquid causes the cells to be patterned to be moved to the corresponding eddy field force balance point above their respective nearest antinodes, so as to perform patterned manipulation on the cells to be patterned according to the preset pattern arrangement.

[0009] Optionally, while applying the preset excitation signal to the thin film resonator, a detection signal of the thin film resonator is also received and detected, and the vibration state of the thin film resonator is determined by the detection signal.

[0010] Optionally, the preset excitation signal is changed to drive the thin film resonator to vibrate in different preset resonance modes, so as to perform patterned manipulation of the cells to be patterned in different preset pattern arrangements.

[0011] Optionally, a vertical distance between the eddy current center of the eddy current field formed by the thin film resonator and the surface of the thin film is greater than or equal to an equivalent diameter of a single cell to be patterned.

[0012] Optionally, two or more thin film resonators arranged in a preset array are integrated and packaged, and a liquid containing the cells to be patterned is set on a preset thin film of the thin film resonator; preset excitation signals are applied to the thin film resonators provided with the liquid containing the cells to be patterned, so as to perform patterned manipulation on the cells to be patterned.

[0013] The present invention also provides a microchip, wherein the microchip adopts any one of the above-mentioned thin film resonator-based cell manipulation methods to perform cell manipulation, and the microchip comprises: a thin film resonator and a liquid placement space;

[0014] The thin film resonator includes a thin film and a resonant driving structure; the thin film is located in the liquid placement space, and the liquid placement space is used to place a liquid containing cells to be patterned; the resonant driving structure is used to drive the thin film resonator to vibrate according to a preset resonant mode to manipulate the cells to be patterned located in the liquid placement space.

[0015] Optionally, the film is a silicon nitride film or an aluminum nitride film.

[0016] Optionally, the length and width of the film are both 100 micrometers to 1000 micrometers.

[0017] Optionally, the microchip includes more than two thin film resonators arranged in a preset array, and each of the thin film resonators is correspondingly provided with a liquid placement space.

[0018] Optionally, the thin film resonator is a MEMS thin film resonator.

[0019] As described above, the cell manipulation method and microchip based on thin film resonator of the present invention have the following beneficial effects:

[0020] The present invention can form an eddy current field in a liquid containing cells to be patterned by controlling the resonant mode of a thin film resonator, thereby generating a Stokes drag force on the cells to be patterned, and realizes rapid movement and pattern manipulation of cells by adjusting the frequency of an electrical signal, thereby improving the speed of cell manipulation while ensuring the accuracy of cell manipulation.

[0021] The present invention achieves cell manipulation by generating an eddy current field in a liquid containing cells to be patterned, thereby avoiding direct contact with cells during manipulation, achieving non-contact cell manipulation, and reducing stimulation or damage caused by contact with cells.

[0022] Since the resonant frequency of the thin film resonator is low, the heating effect on the liquid is minimized, and the influence on the cells during the cell manipulation process is further reduced;

[0023] The present invention can realize batch manufacturing of thin film resonators by utilizing micromachining technology, and can also realize parallel manipulation of a large number of cells, thereby improving the complexity of cell patterning and the manipulation efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 Shown is a schematic diagram of the structure presented by realizing cell patterning in step 2 of the cell manipulation method based on thin film resonator of the present invention.

[0025] Figure 2 Shown is a partial schematic diagram of the eddy current field formed in the cell manipulation method based on thin film resonator of the present invention.

[0026] Figure 3 Shown is a schematic diagram of a three-dimensional modal diagram of a resonant mode obtained in an example of a cell manipulation method based on a thin film resonator of the present invention.

[0027] Figure 4 Shown is a schematic top view of a modal diagram of a resonant mode obtained in an example of a cell manipulation method based on a thin film resonator of the present invention.

[0028] Figure 5 A schematic top view showing the distribution of eddy current fields formed by a thin film resonator as an example of a microchip in the present invention.

[0029] Figure 6 A schematic side view showing the distribution of eddy current fields formed by a thin film resonator as an example of a microchip in the present invention.

[0030] Figure 7 Shown is a schematic diagram of the structure obtained after the eddy current field formed by the thin film resonator of an example of the microchip in the present invention is patterned on the cell.

[0031] Description of Figure Numbers

[0032] 1. Thin film resonator; 2. Cell; 3. Eddy current field; 4. Antinode; 5. Modal diagram; 6. Stokes drag force; 7. Eddy current center. DETAILED DESCRIPTION

[0033] The following describes the embodiments of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.

[0034] For example, when describing the embodiments of the present invention in detail, for the sake of convenience, the schematic diagrams showing the device structure will not be partially enlarged according to the general scale, and the schematic diagrams are only examples, which should not limit the scope of protection of the present invention. In addition, in actual production, the three-dimensional dimensions of length, width and depth should be included.

[0035] For convenience of description, spatially relative terms such as "under", "below", "below", "below", "above", "on", etc. may be used herein to describe the relationship of one element or feature shown in the drawings to other elements or features. It will be understood that these spatially relative terms are intended to encompass other orientations of the device in use or operation in addition to the orientation depicted in the drawings.

[0036] In the context of the present application, a structure in which a first feature is described as being "above" a second feature may include embodiments in which the first and second features are in direct contact, and may also include embodiments in which additional features are formed between the first and second features, such that the first and second features may not be in direct contact.

[0037] It should be noted that the diagrams provided in this embodiment are only used to illustrate the basic concept of the present invention in a schematic manner, and therefore the diagrams only show components related to the present invention rather than being drawn according to the number, shape and size of components in actual implementation. In actual implementation, the type, quantity and proportion of each component may be changed arbitrarily, and the component layout may also be more complex; the quantity range given in the present invention includes the two boundary values ​​of the quantity range by default without special restrictions.

[0038] The cell micromanipulation and patterning technologies in the prior art generally include the following:

[0039] 1) Mechanical operation: mainly through the capillaries fixed on the micro-mechanical arm, sucking cells to move cells; or through the atomic force microscope probe to adhere to cells, move cells or fix cells to form patterns. This type of method requires direct contact with cells, which will affect the physiological state of the cells themselves, and even cause damage and destruction, and the efficiency of manipulating single cells and cells one by one is low;

[0040] 2) Optical manipulation: mainly through focusing laser to irradiate cells, the optical tweezers effect is produced due to the difference in refractive index between cells and the surrounding environment, that is, when the light beam passes through the particle, a resultant force pointing to the focus of the light beam is exerted due to refraction, so that the particle is captured at the focus of the light beam, thereby achieving the movement and patterning of cells. In this type of method, the focused laser will heat or damage the cells. Although the operation accuracy is very high, the patterning efficiency is low. One beam of light can only manipulate one cell, and a large number of beams are required to achieve parallel manipulation and patterning of cells;

[0041] 3) Chemical modification: mainly through patterning a layer of chemical molecules on the surface, using chemical specific binding to capture, fix and pattern cells to form a cell pattern that is the same as the chemical molecule pattern. The manipulation accuracy in this type of method depends on the line width of the chemical molecule modification pattern, and the line width accuracy of the chemical molecule modification pattern is usually at the micron level, which cannot meet many requirements for high-precision cell manipulation; and the chemical modification method has a relatively slow chemical binding process compared to mechanical and optical methods, and once the cells are fixed, the pattern cannot be reconstructed, cleared, or reused;

[0042] 4) Electric field manipulation: mainly uses metal electrode patterns to move cells using the dielectrophoresis effect. Although this method can manipulate a large number of cells at the same time, its manipulation process depends on the conductive properties of cells and solutions, and the electric field can also cause cell damage;

[0043] 5) Magnetic field manipulation: cells are first bound to modified magnetic beads through specific binding, and then the magnetic field is used to manipulate the magnetic beads to achieve cell patterning. This type of method requires the use of magnetic beads, and the number of cells on a single magnetic bead cannot be well controlled;

[0044] 6) Microfluidics: mainly through the PDMS (polydimethylsiloxane) channels, micropores, steps and other structures processed in the microfluidic chip to move, roll, squeeze, stretch and pattern cells; this method, like the mechanical operation method, requires direct contact with the cells, which will stimulate or even damage the cells;

[0045] 7) Surface acoustic wave devices: mainly generate surface acoustic waves of tens or hundreds of megahertz through interdigital electrodes on piezoelectric substrates, use ultrasound to generate acoustic radiation force through materials with different acoustic properties of cells and solutions to push cells to move, and generate standing waves through groups of interdigital electrodes to pattern cells. Although this type of method has the advantages of fast speed and multi-cell parallelization, it has good applications in rapid cell screening and cell manipulation, but long-term ultrasonic vibration will also heat the solution, thereby affecting the cell state and environmental temperature;

[0046] Therefore, existing cell micromanipulation and patterning technologies still find it difficult to achieve rapid, non-destructive, multi-cell parallel cell manipulation effects while minimizing changes in cell status or causing damage.

[0047] The present invention provides a cell manipulation method based on a MEMS (Micro Electro Mechanical Systems) thin film resonator. The cell manipulation method based on a thin film resonator of the present invention will be described in detail below in conjunction with the accompanying drawings. It should be noted that the following sequence does not strictly represent the sequence of the cell manipulation method based on a thin film resonator protected by the present invention, and those skilled in the art may change it according to the actual steps.

[0048] First, step 1 is performed to place a liquid containing cells 2 to be patterned on the thin film of the thin film resonator 1 so that the thin film is located in the liquid.

[0049] Then, step 2 is performed to apply a preset excitation signal to the thin film resonator 1 to drive the thin film of the thin film resonator 1 to vibrate in a preset resonant mode; the resonance of the thin film forms an eddy field 3 in the liquid, and the preset resonant mode of the thin film includes more than two antinodes 4 arranged in a preset pattern, and the antinode 4 is the point where the amplitude of the thin film in the preset resonant mode is the largest. Figure 1 As shown, the eddy field 3 formed by the vibration of the thin film resonator 1 in the liquid moves the cells to be patterned 2 in the liquid to the force balance point of the eddy field 3 above their respective closest antinodes 4, so as to perform patterned manipulation on the cells to be patterned 2 according to a preset pattern arrangement.

[0050] Specifically, the force balance point of the cell 2 in the eddy current field 3 is located directly above the corresponding antinode 4, but due to the influence of actual devices, environment, etc., the actual position of the force balance point may be slightly offset.

[0051] The present invention can obtain a corresponding resonant mode by operating the thin film resonator 1 at its resonant frequency, and control and change the resonant mode by adjusting the resonant frequency, so as to form a patterned cell 2 in a liquid containing the cell 2 to be patterned. Figure 2The eddy current field 3 shown in the figure generates a Stokes drag force 6 on the patterned cell 2, and the frequency adjustment of the electrical signal is used to achieve rapid movement (within seconds) and patterned manipulation of the cell 2, thereby improving the speed of cell 2 manipulation while ensuring the accuracy of cell manipulation; at the same time, the eddy current field 3 is generated in the liquid containing the cell 2 to be patterned to achieve manipulation of the cell 2, thereby avoiding direct contact with the cell 2 during the cell manipulation process, achieving non-contact cell manipulation, and reducing the impact or damage caused by contact with the cell 2; in addition, since the resonant frequency of the thin film resonator 1 is low, the liquid heating effect is significantly reduced; and the thin film resonator can be realized by micromachining technology. 1 is mass-produced to form an array integrated chip to perform patterned parallel manipulation on a large number of cells 2, thereby improving the efficiency of cell pattern manipulation; finally, since the thin film resonator 1 has a variety of resonant modes, the thin film resonator 1 can be made to work in different resonant modes by changing the driving frequency given by the preset excitation signal. The number and position of the antinodes 4 in different resonant modes will change, and the antinodes 4 will determine the position where the cells 2 stay after the force is balanced in the eddy current field 3. Therefore, by controlling the resonant mode, the cells can be manipulated in parallel, and a variety of arrangement modes of cell patterning can be set, including more complex cell pattern arrays, to achieve distribution flexibility of cell manipulation and expand the scope of application.

[0052] Specifically, Figure 3-Figure 4 As shown, the antinode 4 is the mode of the resonant mode obtained by the thin film resonator 1 at the resonant frequency. Figure 5 The position with the largest amplitude.

[0053] Specifically, the liquid containing the cells 2 to be patterned generally needs to be a liquid environment suitable for the survival of the cells 2 to be patterned, such as a PBS (phosphate buffered saline) solution. The liquid environment can be set according to the specific application purpose and requirements of cell manipulation.

[0054] In one embodiment, while applying the preset excitation signal to the thin film resonator 1 , a detection signal of the thin film resonator 1 is received and detected, and the vibration state of the thin film resonator 1 is determined by the detection signal.

[0055] The present invention simultaneously receives and detects the detection signal of the thin film resonator 1, thereby being able to detect in real time whether the thin film resonator 1 is in a preset resonant mode, so as to confirm whether the cell 2 achieves the preset patterned manipulation, thereby improving the accuracy of cell manipulation as a verification step.

[0056] In one embodiment, the preset excitation signal is changed to drive the thin film of the thin film resonator 1 to vibrate in different preset resonance modes, so as to perform patterning manipulation of the cells to be patterned 2 in different preset pattern arrangements.

[0057] The present invention can achieve real-time cell manipulation of different preset pattern arrangements by changing the preset excitation signal, thereby realizing some application scenarios that require different distribution manipulation changes of cells 2, further expanding the applicability of the present solution, and improving the flexibility of use and the convenience of pattern changes.

[0058] In one embodiment, the distribution of the antinodes 4 in the resonant mode of the thin film resonator 1 can be a square array of m rows and n columns, or other required resonant modes. For example, the distance between two adjacent antinodes 4 in the resonant mode is not necessarily equal as in the square array, but is distributed in a fan-shaped ring shape, or other more complex distribution patterns of the antinodes 4 can meet various needs of cell manipulation and patterning. The control of various resonant modes to achieve manipulation and patterning of various arrangements of cells 2 is within the scope of protection of the present invention.

[0059] In one embodiment, the resonant frequency of the preset resonant mode is 10 kHz-1 MHz.

[0060] Preferably, the resonant frequency of the preset resonant mode is 50kHz-500kHz.

[0061] Specifically, the resonant frequency of the preset resonant mode is Wherein γ is a correction coefficient related to the thin film resonator 1 and the liquid parameters, σ is the tensile stress of the film, and ρ is the material density of the film; when the antinodes 4 formed by the resonant mode of the thin film resonator 1 are distributed in a square array, m and n are respectively the number of rows and columns of the square array of antinodes 4 obtained under the corresponding resonant mode, and a and b are respectively the length and width corresponding to the thin film of the thin film resonator 1. It can be seen that by adjusting the size of the film and matching the number of rows and columns of the target square array, the required resonant frequency of the thin film resonator 1 can be determined; when the target square array is determined, the size of the film can be adjusted to ensure that the resonant frequency is not too high, thereby significantly reducing the heating effect caused by the vibration of the thin film resonator 1 and not having a significant impact on the cell 2.

[0062] In one embodiment, the thin film resonator 1 is a MEMS thin film resonator obtained by MEMS process. Specifically, the thin film resonator 1 can also be obtained by other micro-machining processes, among which the MEMS thin film resonator obtained by MEMS process is a better choice as a structure that is easier to miniaturize and mass produce, but the thin film resonator 1 obtained by various micro-machining processes is within the protection scope of the present invention.

[0063] The present invention sets the resonant frequency range of the preset resonant mode, and the size of the MEMS thin film resonator obtained by MEMS process is in the micron order and can be in contact with the solution space, so that the heating effect caused by the vibration of the thin film resonator 1 can be significantly reduced, and there is no significant impact on the cell 2; in particular, compared with the method of using ultrasound (frequency of tens of MHz to hundreds of MHz) with a device size of the centimeter order for cell manipulation in the prior art, the lower frequency and smaller size of the MEMS thin film resonator in the present invention can have a negligible heating effect on the liquid and the cell 2, meeting the requirement of lossless effect.

[0064] In one embodiment, a square array distribution of the antinodes 4 with m=5 and n=5 is obtained.

[0065] In one embodiment, the vertical distance between the eddy current center 7 of the eddy current field 3 formed by the thin film resonator 1 and the surface of the thin film is greater than or equal to the equivalent diameter of a single cell 2 to be patterned.

[0066] Specifically, the equivalent diameter of the cell 2 to be patterned refers to the equivalent of the cell 2 to a micron particle with a fixed and uniform diameter, so as to facilitate the simulation modeling of the cell 2 to be patterned. The equivalent diameter can be the representative size data of the cell 2 obtained by appropriate calculation, such as the average diameter or maximum diameter of the cell 2 to be patterned, and can be set according to the modeling requirements.

[0067] Specifically, the vertical distance between the eddy center 7 and the film surface is Where k is the empirical fitting coefficient, υ is the kinematic viscosity of the liquid, and f m,n is the resonant frequency of the thin film resonator 1. It can be seen that the resonant frequency affects the position of the vortex center 7. Therefore, when determining the resonant frequency, it is necessary not only to determine it according to the required resonant mode, but also to determine it according to the distance range between the film and the liquid vortex center 7 required by the equivalent diameter of the cell 2 to be patterned.

[0068] Specifically, k is approximately equal to 2.8.

[0069] Specifically, the Stokes drag force 6 exerted on the cell 2 in the eddy current field 3 is: Where μ is the dynamic viscosity used to characterize the viscosity of the liquid, d is the equivalent diameter of the cell 2, is the average flow velocity of the cell 2 at each point on the surface of the cell 2 under the action of the eddy flow field 3. Specifically, F d The order of magnitude can generally reach the order of pN-nN depending on the film amplitude.

[0070] The present invention also provides a microchip, wherein the microchip adopts any one of the above-mentioned cell manipulation methods based on the thin film resonator 1 to perform cell manipulation, and the microchip comprises: a thin film resonator 1 and a liquid placement space;

[0071] The thin film resonator 1 includes a thin film and a resonant driving structure; the thin film is located in the liquid placement space, and the liquid placement space is used to place a liquid containing cells to be patterned 2; the resonant driving structure is used to drive the thin film resonator 1 to vibrate according to a preset resonant mode to manipulate the cells to be patterned 2 located in the liquid placement space.

[0072] The present invention sets a liquid placement space so that the thin film of the thin film resonator 1 is located in the liquid placement space, so that the thin film can form an eddy field 3 in the liquid placed in the liquid placement space through its own resonant mode, thereby utilizing the Stokes drag force 6 of the eddy field 3 on the cell 2 in the liquid to realize manipulation of the cell 2 to be patterned in the liquid; at the same time, the liquid placement space is utilized to place the cell 2 to be patterned and the thin film at the same time in an environment where they can interact with each other, but the cell 2 to be patterned is not in direct contact with the thin film, thereby realizing non-destructive manipulation of the cell 2.

[0073] In one embodiment, the film is a silicon nitride film.

[0074] The present invention uses silicon nitride film as the film material of the thin film resonator 1, which has the advantages of low stress and stable properties compared with other thin film materials, and can improve the performance reliability and stability of the microchip.

[0075] In one embodiment, the material of the film may also be various suitable thin film resonator thin film materials such as silicon oxide, silicon, aluminum nitride, etc., which can be set according to requirements and are all within the protection scope of the present invention.

[0076] In one embodiment, the length and width of the film are both 100 micrometers to 1000 micrometers.

[0077] Specifically, the length and width of the film refer to the lengths in two other mutually perpendicular spatial directions perpendicular to the thickness direction; the length and width of the film may also be selected from other suitable ranges according to requirements, all within the protection scope of the present invention.

[0078] In one embodiment, in a thin film resonator 1, the length and width of the thin film are both 500 microns, and the density ρ=3200 kg / m 3 , the film tensile stress σ=300MPa. To obtain the resonant mode of m=n=5, the resonant frequency f of the thin film resonator 1 in the liquid environment (such as PBS solution) is 5,5 ≈600kHz, such as Figure 3-Figure 4 The simulation results of the thin film resonator 1 show the mode of the resonant mode of the thin film resonator 1 at this frequency. Figure 5 , which has 5 rows and 5 columns of antinodes 4 in the length and width directions respectively;

[0079] Then in Figure 3-Figure 4 Based on the simulation results of the resonant mode of the thin film resonator 1, the eddy field 3 formed by the thin film of the MEMS resonant thin film device 1 on the surface liquid can be simulated by using the Navier-Stokes equations. Figure 5 The figure shows a top view of the distribution of the eddy current field 3 on the thin film surface of the thin film resonator 1. Figure 6 The figure shows a side view of the distribution of the eddy current field 3 on the film surface of the thin film resonator 1 (the direction of the arrow shows the movement direction of the eddy current field 3); in the side view of the distribution of the eddy current field 3 on the film surface of the thin film resonator 1, it can be clearly seen that the distance between the eddy center 7 of the eddy current field 3 and the film surface is about 15μm; in the top view of the distribution of the eddy current field 3 on the film surface of the thin film resonator 1, it can be seen that the direction of the flow field close to the film surface is all pointing to the film antinode 4; the cell 2 is equivalent to a microparticle with a diameter of 15μm (such as Figure 7 The black ball moves toward the corresponding vortex center 7 in the liquid above the wave crest (or wave trough), and reaches force balance at the position of the corresponding vortex center 7 in the liquid above each wave crest (or wave trough), as shown in FIG. Figure 7 As shown, the patterned cells 2 are formed, and the entire formation process can be completed in a few seconds. The above results prove that the thin film resonator 1 can control the resonant mode through the resonant frequency, thereby using the Stokes drag force generated by the thin film in the liquid to achieve rapid, non-destructive, non-contact and parallel manipulation and patterning of micro-scale particles and cells 2.

[0080] In one embodiment, the microchip includes more than two thin film resonators 1 arranged in a preset array, and each of the thin film resonators 1 is correspondingly provided with a liquid placement space.

[0081] The present invention provides a plurality of thin film resonators 1 arranged in a preset array, so that the microchip can realize parallel manipulation of a greater number of cells 2, thereby improving the cell manipulation efficiency of the microchip.

[0082] In one embodiment, some different thin film resonators 1 may be set in different resonance modes, so as to achieve the effect of performing partitioned personalized manipulation on the patterned cells 2, further improving the flexibility of cell manipulation.

[0083] In one embodiment, the liquid placement space is a microchannel structure, and the microchannel structure is used to guide the liquid containing the cells 2 to be patterned to the surface of the film.

[0084] The present invention sets a microfluidic channel structure as a liquid placement space, and can realize the preparation of the liquid placement space through a microstructure processing technology. At the same time, the setting of the microfluidic channel structure is also more flexible, thereby improving the process compatibility and design convenience of the microchip.

[0085] In one embodiment, the thin film resonator 1 is a MEMS thin film resonator.

[0086] By setting the thin film resonator 1 as a MEMS thin film resonator, the present invention can use the existing MEMS process to achieve miniaturized design and mass production of the thin film resonator 1, which is conducive to further miniaturization of microchips and improvement of production efficiency.

[0087] In one embodiment, when the microchip includes m thin film resonators 1 arranged in a preset array, the liquid placement spaces (microchannel structures) of the preset n thin film resonators 1 are interconnected, m is an integer greater than or equal to 2, and n is an integer greater than or equal to 2 and less than or equal to m.

[0088] The present invention arranges n thin film resonators 1 to be interconnected in microchannel structures, so that the thin film resonators 1 can be fed with the same type of liquid to manipulate the cells 2, thereby improving the convenience of performing partitioned personalized cell manipulation on the microchip.

[0089] In summary, the cell manipulation method and microchip based on thin film resonator of the present invention can form an eddy current field in a liquid containing cells to be patterned by controlling the resonant mode of the thin film resonator, thereby generating a Stokes drag force on the cells to be patterned, and realizing rapid movement and patterned manipulation of the cells by adjusting the frequency and amplitude of the electrical signal, thereby improving the speed of cell manipulation while ensuring the accuracy of cell manipulation; at the same time, the manipulation of the cells is realized by generating an eddy current field in the liquid containing the cells to be patterned, thereby avoiding direct contact with the cells during the cell manipulation process, realizing non-contact cell manipulation, and reducing the impact or damage to the cells caused by contact with the cells during the cell manipulation process; in addition, since the resonant frequency of the thin film resonator is low, the impact of the heating effect generated by the vibration on the cells is significantly reduced; finally, the micromachining process can be used to realize mass production of thin film resonators, and a large number of cells can be patterned and manipulated in parallel, thereby improving the efficiency of cell patterning manipulation.

[0090] Therefore, the present invention effectively overcomes various shortcomings in the prior art and has high industrial utilization value.

[0091] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. A cell manipulation method based on a thin film resonator, characterized in that: The cell manipulation method comprises: Placing a liquid containing cells to be patterned on a thin film of a thin film resonator so that the thin film is located in the liquid; A preset excitation signal is applied to the thin film resonator to drive the thin film resonator to vibrate in a preset resonant mode; the resonance of the thin film forms an eddy field in the liquid, and the preset resonant mode of the thin film includes two or more antinodes arranged in a preset pattern, and the antinode is the point where the amplitude of the thin film in the preset resonant mode is the largest; the eddy field formed in the liquid moves the cells to be patterned to the corresponding eddy field force balance point above each nearest antinode, so as to perform patterned manipulation on the cells to be patterned according to the preset pattern arrangement.

2. The cell manipulation method based on thin film resonator according to claim 1, characterized in that: While applying the preset excitation signal to the thin film resonator, a detection signal of the thin film resonator is received and detected, and the vibration state of the thin film resonator is determined by the detection signal.

3. The cell manipulation method based on thin film resonator according to claim 1, characterized in that: The preset excitation signal is changed to drive the thin film resonator to vibrate in different preset resonance modes, and pattern manipulation of the cells to be patterned is performed in different preset pattern arrangements.

4. The cell manipulation method based on thin film resonator according to claim 1, characterized in that: The vertical distance between the eddy current center of the eddy current field formed by the thin film resonator and the surface of the thin film is greater than or equal to the equivalent diameter of a single cell to be patterned.

5. The cell manipulation method based on thin film resonator according to any one of claims 1 to 4, characterized in that: Two or more thin film resonators arranged in a preset array are integrated and manufactured and packaged, and a liquid containing the cells to be patterned is set on the preset thin film of the thin film resonator; preset excitation signals are applied to the thin film resonators provided with the liquid containing the cells to be patterned, so as to perform patterned manipulation on the cells to be patterned.

6. A microchip, characterized in that: The microchip adopts the cell manipulation method based on thin film resonator described in any one of claims 1 to 5 to perform cell manipulation, and the microchip includes: a thin film resonator and a liquid placement space; the thin film resonator includes a thin film and a resonant driving structure; the thin film is located in the liquid placement space, and the liquid placement space is used to place a liquid containing cells to be patterned; the resonant driving structure is used to drive the thin film resonator to vibrate according to a preset resonant mode to manipulate the cells to be patterned located in the liquid placement space.

7. The microchip according to claim 6, characterized in that The film is a silicon nitride film or an aluminum nitride film.

8. The microchip according to claim 6, characterized in that The length and width of the film are both 100 micrometers to 1000 micrometers.

9. The microchip according to claim 6, characterized in that: The microchip includes more than two thin film resonators arranged in a preset array, and each of the thin film resonators is correspondingly provided with a liquid placement space.

10. The microchip according to any one of claims 6 to 9, characterized in that: The thin film resonator is a MEMS thin film resonator.

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